Methods and apparatus for selective tissue ablation

ABSTRACT

Catheter systems and methods for the selective and rapid application of DC voltage to drive irreversible electroporation are disclosed herein. In some embodiments, an apparatus includes a voltage pulse generator and an electrode controller. The voltage pulse generator is configured to produce a pulsed voltage waveform. The electrode controller is configured to be operably coupled to the voltage pulse generator and a medical device including a series of electrodes. The electrode controller includes a selection module and a pulse delivery module. The selection module is configured to select a subset of electrodes from the series of electrodes. The selection module is configured identify at least one electrode as an anode and at least one electrode as a cathode. The pulse delivery module is configured to deliver an output signal associated with the pulsed voltage waveform to the subset of electrodes.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/341,512, entitled “METHODS AND APPARATUS FOR SELECTIVE TISSUEABLATION”, filed Nov. 2, 2016, now abandoned, which is a continuation ofPCT Application No. PCT/US2015/029734, entitled “METHODS AND APPARATUSFOR SELECTIVE TISSUE ABLATION”, filed May 7, 2015, which claims priorityto U.S. Provisional Application Ser. No. 61/996,390, entitled “Methodand Apparatus for Rapid and Selective Tissue Ablation,” filed May 7,2014, the entire disclosures of which are incorporated herein byreference.

BACKGROUND

The embodiments described herein relate generally to medical devices fortherapeutic electrical energy delivery, and more particularly to systemsand methods for delivering electrical energy in the context of ablatingtissue rapidly and selectively by the application of suitably timedpulsed voltages that generate irreversible electroporation of cellmembranes.

The past two decades have seen advances in the technique ofelectroporation as it has progressed from the laboratory to clinicalapplications. Known methods include applying brief, high voltage DCpulses to tissue, thereby generating locally high electric fields,typically in the range of hundreds of Volts/centimeter. The electricfields disrupt cell membranes by generating pores in the cell membrane,which subsequently destroys the cell membrane and the cell. While theprecise mechanism of this electrically-driven pore generation (orelectroporation) awaits a detailed understanding, it is thought that theapplication of relatively large electric fields generates instabilitiesin the phospholipid bilayers in cell membranes, as well as mitochondria,causing the occurrence of a distribution of local gaps or pores in themembrane. If the applied electric field at the membrane exceeds athreshold value, typically dependent on cell size, the electroporationis irreversible and the pores remain open, permitting exchange ofmaterial across the membrane and leading to apoptosis or cell death.Subsequently, the surrounding tissue heals in a natural process.

While pulsed DC voltages are known to drive electroporation under theright circumstances, the examples of electroporation applications inmedicine and delivery methods described in the prior art do not discussspecificity of how electrodes are selected to accomplish the desiredablation.

There is a need for selective energy delivery for electroporation andits modulation in various tissue types, as well as pulses that permitrapid action and completion of therapy delivery. There is also a needfor more effective generation of voltage pulses and control methods, aswell as appropriate devices or tools addressing a variety of specificclinical applications. Such more selective and effective electroporationdelivery methods can broaden the areas of clinical application ofelectroporation including therapeutic treatment of a variety of cardiacarrhythmias.

SUMMARY

Catheter systems and methods are disclosed for the selective and rapidapplication of DC voltage to drive electroporation. In some embodiments,an apparatus includes a voltage pulse generator and an electrodecontroller. The voltage pulse generator is configured to produce apulsed voltage waveform. The electrode controller is configured to beoperably coupled to the voltage pulse generator and a medical deviceincluding a series of electrodes. The electrode controller includes aselection module and a pulse delivery module. The selection module isconfigured to select a subset of electrodes from the series ofelectrodes. The selection module is configured identify at least oneelectrode as an anode and at least one electrode as a cathode. The pulsedelivery module is configured to deliver an output signal associatedwith the pulsed voltage waveform to the subset of electrodes.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of a portion of a catheter with multipleelectrodes disposed along its shaft and wrapped around the pulmonaryveins of the heart such that the portion of the catheter is placed inthe epicardial space of the heart.

FIG. 2A is a schematic illustration of an irreversible electroporationsystem that includes a DC voltage/signal generator, a controller capableof being configured to apply voltages to selected subsets of electrodeswith independent subset selections for anode and cathode.

FIG. 2B is a schematic illustration of an irreversible electroporationsystem that includes a DC voltage/signal generator and a controlleraccording to an embodiment.

FIG. 3 is an illustration of an ECG waveform showing the refractoryperiods during atrial and ventricular pacing, and the time windows forirreversible electroporation ablation.

FIG. 4 is a schematic illustration of a user interface according to anembodiment showing various configurations for subsets of electrodes onthe catheter to be identified as anodes or cathodes, and the ablationvectors therebetween.

FIG. 5 is a schematic illustration of a user interface according to anembodiment, indicating the electrodes that are active and wrapped aroundthe pulmonary veins of a patient anatomy, and that can be activelyavailable for selection in bipolar ablation.

FIG. 6 is a schematic illustration of a user interface according to anembodiment that illustrates a method of ablating along a cardiac isthmusline using two catheters, one of which is wrapped around the pulmonaryveins.

FIG. 7 is a schematic illustration of a user interface according to anembodiment that illustrates a method of focal ablation, wherein nearbyelectrodes on the same catheter are used for bipolar ablation withirreversible electroporation to ablate a region of contacting tissue atthe distal catheter end, and showing a depth selection button that canbe used to selectively adjust an ablation parameter.

FIG. 8 is a schematic illustration according to an embodiment, showing agraphic window for selection of type of pacing to be used forelectroporation therapy delivery.

FIG. 9 is a schematic illustration of a user interface according to anembodiment, showing a graphic window with parameters associated with aselected pacing type.

FIG. 10 is a schematic illustration of a user interface that illustratesa method of selecting anode electrode subsets and cathode electrodesubsets on two different catheters according to an embodiment.

FIG. 11 is a schematic illustration of a user interface that illustratesa method of selecting a single anode electrode and a single selectedcathode electrode on the same catheter according to an embodiment.

FIG. 12 is a schematic illustration of a waveform generated by theirreversible electroporation system and methods according to anembodiment, showing a balanced square wave.

FIG. 13 is a schematic illustration of a waveform generated by theirreversible electroporation system and methods according to anembodiment, showing a balanced biphasic square wave.

FIG. 14 is a schematic illustration of a waveform generated by theirreversible electroporation system and methods according to anembodiment, showing a progressive balanced biphasic square wave.

FIG. 15 is a schematic illustration of a signal generator according toan embodiment, showing a capacitor bank connected to a set of switches.

FIG. 16 is a schematic illustration of a voltage pulse-time plotproduced by a high voltage DC signal generator according to anembodiment.

FIG. 17 is a schematic depiction of a sequence of three biphasic pulsesdelivered by a voltage generator and using methods according to anembodiment, showing a pre-polarizing negative voltage pulse followed bya positive polarizing pulse.

FIG. 18A is a schematic illustration of a distal portion of a catheterhaving two electrodes functioning as a cathode and an anode according toan embodiment.

FIG. 18B is a schematic illustration of a distal portion of a catheteraccording to an embodiment having a recessed distal anode electrode, theillustration showing the current flow between electrodes.

FIG. 18C is a schematic illustration of a distal portion of a catheteraccording to an embodiment, where electric field lines near the distalend of the catheter are schematically shown together with a region offocal ablation in tissue.

FIG. 18D is a schematic illustration of a distal portion of a catheteraccording to an embodiment, where the catheter lumen has flowing fluid,possibly with ultrasonic waves conducted through the fluid, and thedistal anode electrode has channels for fluid flow to exit the distalend of the catheter.

FIG. 19A is an illustration of the simulation geometry showing ageometric model of the distal portion of a catheter and surroundingtissue types.

FIG. 19B is an illustration of the distal portion of a catheter with aproximal electrode disposed externally on the shaft of the catheter anda distal electrode that is recessed and disposed on the inner side ofthe shaft of the catheter.

FIG. 19C is an illustration of a longitudinal cross-section of thesimulation geometry showing distal catheter geometry and tissue geometrytogether with electric field intensity contours for the case when theproximal electrode is disposed externally on the shaft of the catheterand the distal electrode is recessed and disposed on the inner side ofthe shaft of the catheter, according to an embodiment.

FIG. 19D is an illustration of a longitudinal cross-section of thesimulation geometry showing distal catheter geometry and tissue geometrytogether with electric field intensity contours for the case when theproximal and distal electrodes are both disposed externally on the shaftof the catheter, according to an embodiment.

FIG. 20 is a schematic illustration of a balloon catheter according toan embodiment, where a balloon structure with an insulating exterior islocated between anode and cathode electrodes for electroporation voltagedelivery.

FIG. 21A is a schematic illustration of a balloon catheter according toan embodiment, where a balloon structure with an insulating exterior andwith at least one ultrasonic transducer is located between anode andcathode electrodes for electroporation voltage delivery.

FIG. 21B is a schematic illustration of a balloon catheter according toan embodiment, where an annular ablation region abutting a vessel isshown.

FIG. 22 is a schematic illustration of a basket ablation catheter forelectroporation energy delivery according to an embodiment.

DETAILED DESCRIPTION

Systems and methods are disclosed for the selective and rapidapplication of DC voltage to drive electroporation. In some embodiments,the irreversible electroporation system described herein includes a DCvoltage/signal generator and a controller capable of being configured toapply voltages to a selected multiplicity or a subset of electrodes,with anode and cathode subsets being selected independently. Thecontroller is additionally capable of applying control inputs wherebyselected pairs of anode-cathode subsets of electrodes can besequentially updated based on a pre-determined sequence.

In some embodiments, an irreversible electroporation system includes aDC voltage/signal generator and a controller capable of being configuredto apply voltages to a selected multiplicity or a subset of electrodes,with independent subset selections for anode and cathode. Further, thecontroller is capable of applying control inputs whereby selected pairsof anode-cathode subsets of electrodes can be sequentially updated basedon a pre-determined sequence. The generator can output waveforms thatcan be selected to generate a sequence of voltage pulses in eithermonophasic or biphasic forms and with either constant or progressivelychanging amplitudes. In one embodiment, a DC voltage pulse generationmechanism is disclosed that can use amplified voltage spikes generatedby the action of a switch connected to a capacitor bank, resulting in abiphasic, asymmetric micro pulse waveform for cardiac ablation where thefirst phase provides a brief pre-polarizing pulse that is followed by afinishing pulse in the second phase. Such pre-polarization can result inmore effective pulsed voltage electroporation delivery. Methods ofcontrol and DC voltage application from a generator capable of selectiveexcitation of sets of electrodes are disclosed. Devices are disclosedfor more effective DC voltage application through ionic fluid irrigationand ultrasonic agitation, possibly including insulating balloonconstructions to displace electrodes from collateral structures, and foruse in intravascular applications. Such devices for generatingirreversible electroporation can be utilized in cardiac therapyapplications such as ablation to treat Ventricular Tachycardia (VT) aswell as in intravascular applications. In some embodiments, the use oftemperature to selectively ablate tissue is described, as the thresholdof irreversible electroporation is temperature-dependent, utilizingfocused kinetic energy to select the predominant tissue type or regionit is desired to ablate

In some embodiments, an apparatus includes a voltage pulse generator andan electrode controller. The voltage pulse generator is configured toproduce a pulsed voltage waveform. The electrode controller isconfigured to be operably coupled to the voltage pulse generator and amedical device including a series of electrodes. The electrodecontroller is implemented in at least one of a memory or a processor,and includes a selection module and a pulse delivery module. Theselection module is configured to select a subset of electrodes from theseries of electrodes. The selection module is configured identify atleast one electrode as an anode and at least one electrode as a cathode.The pulse delivery module is configured to deliver an output signalassociated with the pulsed voltage waveform to the subset of electrodes.

In some embodiments, an apparatus includes a voltage pulse generator andan electrode controller. The voltage pulse generator is configured toproduce a pulsed voltage waveform. The electrode controller isconfigured to be operably coupled to the voltage pulse generator and amedical device including a series of electrodes. The electrodecontroller is implemented in at least one of a memory or a processor,and includes a selection module and a pulse delivery module. Theselection module is configured to select a set of anode/cathode pairs,each anode/cathode pair including at least one anode electrode and atleast one cathode electrode. In some embodiments, for example, theanode/cathode pair can include one anode and multiple cathodes (orvice-versa). The pulse delivery module is configured to deliver anoutput signal associated with the pulsed voltage waveform to theplurality of anode/cathode pairs according to a sequential pattern.

In some embodiments, a non-transitory processor readable medium storingcode representing instructions to be executed by a processor includescode to cause the processor to identify a set of anode/cathode pairsfrom a set of electrodes of a multi-electrode catheter. Themulti-electrode catheter is configured to be disposed about a portion ofa heart, and at least one anode/cathode pair includes at least one anodeelectrode and at least one cathode electrode. The code further includescode to convey a pacing signal to a pacing lead configured to beoperatively coupled to the heart. The code further includes code toreceive an electrocardiograph signal associated with a function of theheart. The code further includes code to deliver a pulsed voltagewaveform to the set of anode/cathode pairs according to a sequentialpattern.

In some embodiments, a method includes identifying, via a selectionmodule of an electrode controller, a set of anode/cathode pairs from aset of electrodes of a multi-electrode catheter. The multi-electrodecatheter is configured to be disposed about a portion of a heart. Atleast one anode/cathode pair includes at least one anode electrode andat least one cathode electrode. A pacing signal is conveyed to a pacinglead configured to be operatively coupled to the heart. The methodfurther includes receiving, at a feedback module of the electrodecontroller, an electrocardiograph signal associated with a function ofthe heart. The method further includes delivering, via a pulse deliverymodule of the electrode controller, a pulsed voltage waveform to the setof anode/cathode pairs according to a sequential pattern.

In some embodiments, an apparatus includes a signal generator for thegeneration of DC voltage pulses. The signal generator is configured toproduce a biphasic waveform having a pre-polarizing pulse followed by apolarizing pulse. The pre-polarizing pulse is generated by utilizingvoltage spikes generated from switching on a discharge of a capacitorbank.

In some embodiments, an apparatus includes a catheter shaft, a cathodeelectrode and an anode electrode. The catheter shaft has an outer sideand an inner side. The cathode electrode is coupled to a distal endportion of the catheter shaft such that a cathode surface is exposed onthe outer side of the catheter shaft. The anode electrode is coupled tothe distal end portion distal relative to the cathode electrode. Theanode electrode is recessed within the catheter shaft and coupled to thecatheter shaft such that an anode surface is exposed on the inner sideof the catheter shaft.

In some embodiments, an apparatus includes a catheter shaft, aninflatable balloon, a first electrode and a second electrode. Thecatheter shaft has a distal end portion. The inflatable balloon iscoupled to the distal end portion. An outer surface of the balloon is anelectrical insulator. The first electrode is coupled to a proximal sideof the balloon, and the second electrode is coupled to a distal side ofthe balloon.

In some embodiments, an apparatus includes a catheter shaft having adistal end portion, an expandable basket structure, a first electrode, asecond electrode, and a set of spherical electrodes. The expandablebasket structure is coupled to the distal end portion of the cathetershaft. The first electrode coupled to a proximal side of the expandablebasket structure. The second electrode is coupled to a distal side ofthe expandable basket structure. The set of spherical electrodes iscoupled to a corresponding set of rounded corners of the expandablebasket structure.

As used in this specification, the singular forms “a,” “an” and “the”include plural referents unless the context clearly dictates otherwise.Thus, for example, the term “a member” is intended to mean a singlemember or a combination of members, “a material” is intended to mean oneor more materials, “a processor” is intended to mean a single processoror multiple processors; and “memory” is intended to mean one or morememories, or a combination thereof.

As used herein, the terms “about” and “approximately” generally meanplus or minus 10% of the value stated. For example, about 0.5 wouldinclude 0.45 and 0.55, about 10 would include 9 to 11, about 1000 wouldinclude 900 to 1100.

As shown in FIG. 1, in some embodiments a Pulmonary Vein isolation (PVisolation) ablation catheter device 15 with a multiplicity of electrodes(indicated by dark bands such as those marked as 17) disposed along itsmid-section is wrapped in the epicardial space around the pulmonaryveins 10, 11, 12 and 13 of a heart 7 in a subject or patient anatomy,with the ends 8 and 9 of the mid-section extending out and away toeventually emerge from the patient's chest. The ablation catheter 15 andany of the catheters described herein can be similar to the ablationcatheters described in PCT Publication No. WO2014/025394, entitled“Catheters, Catheter Systems, and Methods for Puncturing Through aTissue Structure,” filed on Mar. 14, 2013 (“the '394 PCT Application),which is incorporated herein by reference in its entirety. The ablationcatheter 15 can be disposed about the pulmonary veins 10, 11, 12 and 13using any suitable procedure and apparatus. For example, in someembodiments, the ablation catheter 15 can be disposed about thepulmonary veins 10, 11, 12 and 13 and/or the heart 7 using a puncturingapparatus disposed via a subxiphoid pericardial access location and aguidewire-based delivery method as described in the '394 PCTApplication. After the ends 8 and 9 of the mid-section extend and emergeout of the patient chest they can be cinched together to effectivelyhold the catheter in place or position.

A DC voltage for electroporation can be applied to subsets of electrodesidentified as anode and cathode, respectively, on approximately oppositesides of the closed contour defined by the shape of the catheter 15around the pulmonary veins. The DC voltage is applied in brief pulsessufficient to cause irreversible electroporation. In any of the systemsand methods described herein, the pulse or waveform can be in the rangeof 0.5 kV to 10 kV and more preferably in the range 1 kV to 2.5 kV, sothat a threshold electric field value of around 200 Volts/cm iseffectively achieved in the cardiac tissue to be ablated. In someembodiments, the marked electrodes can be automatically identified, ormanually identified by suitable marking, on an X-ray or fluoroscopicimage obtained at an appropriate angulation that permits identificationof the geometric distance between anode and cathode electrodes, or theirrespective centroids. In one embodiment, the DC voltage generatorsetting for irreversible electroporation is then automaticallyidentified by the electroporation system based on this distance measure.In an alternate embodiment, the DC voltage value is selected directly bya user from a suitable dial, slider, touch screen, or any other userinterface. The DC voltage pulse results in a current flowing between theanode and cathode electrodes on opposite sides of the contour defined bythe catheter shape, with said current flowing through the cardiac walltissue and through the intervening blood in the cardiac chamber, withthe current entering the cardiac tissue from the anode and returningback through the cathode electrodes. The forward and return currentpaths (leads) are both inside the catheter. Areas of cardiac wall tissuewhere the electric field is sufficiently large for irreversibleelectroporation are ablated during the DC voltage pulse application. Thenumber of electrodes on the PV isolation ablation catheter can be in therange between 8 and 50, and more preferably in the range between 15 and40.

A schematic diagram of the electroporation system according to anembodiment is shown in FIG. 2A. The system includes a DC voltage/signalgenerator 23 that is driven by a controller unit 21 that interfaces witha computer device 24 by means of a two-way communication link 29. Thecontroller can perform channel selection and routing functions forapplying DC voltages to appropriate electrodes that have been selectedby a user or by the computer 24, and apply the voltages via amultiplicity of leads (shown collectively as 26) to a catheter device22. The catheter device can be any of the catheters shown and describedherein or in the '394 PCT Application. Some leads from the controller 21could also carry pacing signals to drive pacing of the heart through aseparate pacing device (not shown). The catheter device can also sendback information such as ECG (electrocardiograph) recordings or datafrom other sensors back to the controller 21 as indicated by the datastream 25, possibly on separate leads. While the DC voltage generator 23sends a DC voltage to the controller 21 through leads 27, the voltagegenerator is driven by control and timing inputs 28 from the controllerunit 21.

In some embodiments, the electrode controller can include one or moremodules and can automatically perform channel selection (e.g.,identification of a subset of electrodes to which the voltage pulseswill be applied), identification of the desired anode/cathode pairs, orthe like. For example, FIG. 2B shows an electroporation system accordingto an embodiment that includes an electrode controller 900 and a signalgenerator 925. The electrode controller 900 is coupled to a computer 920or other input/output device, and is configured to be operable coupledto a medical device 930. The medical device 930 can be one or moremulti-electrode catheters, of the types shown and described herein.Further the medical device 930 can be coupled to, disposed about and/orin contact with a target tissue, such as the heart H. In this manner, asdescribed herein, the electroporation system, including the electrodecontroller 900 and the signal generator 925, can deliver voltage pulsesto the target tissue for therapeutic purposes.

The controller 900 can include a memory 911, a processor 910, and aninput/output module (or interface) 901. The controller 900 can alsoinclude a pacing module 902, a feedback module 905, a pulse deliverymodule 908, and a selection module 912. The electrode controller 900 iscoupled to a computer 920 or other input/output device via theinput/output module (or interface) 901.

The processor 910 can be any processor configured to, for example, writedata into and read data from the memory 911, and execute theinstructions and/or methods stored within the memory 911. Furthermore,the processor 910 can be configured to control operation of the othermodules within the controller (e.g., the pacing module 902, the feedbackmodule 905, the pulse delivery module 908, and the selection module912). Specifically, the processor can receive a signal including userinput, impedance, heart function or the like information and determine aset of electrodes to which voltage pulses should be applied, the desiredtiming and sequence of the voltage pulses and the like. In otherembodiments, the processor 910 can be, for example, anapplication-specific integrated circuit (ASIC) or a combination ofASICs, which are designed to perform one or more specific functions. Inyet other embodiments, the microprocessor can be an analog or digitalcircuit, or a combination of multiple circuits.

The memory device 910 can be any suitable device such as, for example, aread only memory (ROM) component, a random access memory (RAM)component, electronically programmable read only memory (EPROM),erasable electronically programmable read only memory (EEPROM),registers, cache memory, and/or flash memory. Any of the modules (thepacing module 902, the feedback module 905, the pulse delivery module908, and the selection module 912) can be implemented by the processor910 and/or stored within the memory 910.

As shown, the electrode controller 900 operably coupled to the signalgenerator 925. The signal generator includes circuitry, componentsand/or code to produce a series of DC voltage pulses for delivery toelectrodes included within the medical device 930. For example, in someembodiments, the signal generator 925 can be configured to produce abiphasic waveform having a pre-polarizing pulse followed by a polarizingpulse. The signal generator 925 can be any suitable signal generator ofthe types shown and described herein.

The pulse delivery module 908 of the electrode controller 900 includescircuitry, components and/or code to deliver an output signal associatedwith the pulsed voltage waveform produced by the signal generator 925.This signal (shown as signal 909) can be any signal of the types shownand described herein, and can be of a type and/or have characteristicsto be therapeutically effective. In some embodiments, the pulse deliverymodule 908 receives input from the selection module 912, and cantherefore send the signal 909 to the appropriate subset of electrodes,as described herein.

The selection module 912 includes circuitry, components and/or code toselect a subset of electrodes from the electrodes included within themedical device 930, as described herein. In some embodiments, theselection module 912 is configured identify at least one electrode fromthe subset of electrodes as an anode and at least one electrode from thesubset of electrodes as a cathode. In some embodiments, the selectionmodule 912 is configured to select a subset of electrodes from more thanone medical device 930, as described herein.

In some embodiments, the selection module 912 can select the subset ofelectrodes based on input received from the user via the input/outputmodule 901. For example, in some embodiments, the user can usevisualization techniques or other methods to identify the desiredelectrodes, and can manually enter those electrodes, as describedherein.

In other embodiments, the selection module 912 is configured to selectthe subset of electrodes based on a predetermined schedule of the set ofelectrodes. For example, in some embodiments, the electrode controller900 can be configured accommodate different medical devices 930 havingdifferent numbers and/or types of electrodes. In such embodiments, theselection module 912 can retrieve a predetermined schedule of electrodesto which a series of voltage pulses can be applied, based on thespecific type of medical device 930.

In yet other embodiments, the selection module 912 is configured toselect the subset of electrodes automatically based on at least one ofan impedance associated with the subset of electrodes, a distancebetween the first electrode and the second electrode, and acharacteristic associated with a target tissue. For example, in someembodiments, the electrode controller 900 includes the feedback module905 that can receive feedback from the medical device 930 (as identifiedby the signal 906). The feedback module 905 includes circuitry,components and/or code to determine an impedance between variouselectrodes (as described herein). Thus, in such embodiments, theselection module 912 can select the subset of electrodes automaticallybased the impedance.

In some embodiments, the electrode controller 900 optionally includesthe pacing module 902. The pacing module 902 includes circuitry,components and/or code to produce a pacing signal (identified as signal903) that can be delivered to the target tissue (or heart) via a pacinglead. As described herein, the pacing module 902 can facilitate anysuitable “mode” of operation desired, such as a standard pacing, anoverdrive pacing option (for pacing at a faster-than-normal heart rate),an external trigger option (for pacing from an externally generatedtrigger), and a diagnostic pacing option.

As shown in FIG. 3, given atrial or ventricular pacing inputs to theheart (e.g., from the pacing module 902 of the electrode controller900), the resulting ECG waveform 32 has appropriate respectiverefractory time intervals 33 and 34 respectively, during which there aresuitable time windows for application of irreversible electroporation asindicated by 35 and 36. The application of cardiac pacing results in aperiodic, well-controlled sequence of electroporation time windows.Typically, this time window is of the order of hundreds of microsecondsto about a millisecond or more. During this window, multiple DC voltagepulses can be applied to ensure that sufficient tissue ablation hasoccurred. The user can repeat the delivery of irreversibleelectroporation over several successive cardiac cycles for furtherconfidence. Thus, in some embodiments, a feedback module (e.g., feedbackmodule 905) can receive the electrocardiograph signal, and a pulsedelivery module (e.g., pulse delivery module 908) can deliver the outputsignal to the subset of electrodes during a time window associated withat least one a pacing signal or the electrocardiograph signal.

In some embodiments, the ablation controller and signal generator can bemounted on a rolling trolley, and the user can control the device usinga touchscreen interface that is in the sterile field. Referring to FIG.2B, in such embodiments, the computer 920 can be a touchscreen device.The touchscreen can be for example an LCD touchscreen in a plastichousing mountable to a standard medical rail or post and can be used toselect the electrodes for ablation and to ready the device to fire. Theinterface can for example be covered with a clear sterile plastic drape.The operator can select the number of electrodes involved in anautomated sequence. The touch screen graphically shows the cathetersthat are attached to the controller. In one embodiment the operator canselect electrodes from the touchscreen with appropriate graphicalbuttons. The operator can also select the pacing stimulus protocol(either internally generated or externally triggered) from theinterface. Once pacing is enabled, and the ablation sequence isselected, the operator can initiate or verify pacing. Once the operatorverifies that the heart is being paced, the ablation sequence can beinitiated by holding down a hand-held trigger button that is in thesterile field. The hand-held trigger button can be illuminated red toindicate that the device is “armed” and ready to ablate. The triggerbutton can be compatible for use in a sterile field and when attached tothe controller can be illuminated a different color, for example white.When the device is firing, the trigger button flashes in sequence withthe pulse delivery in a specific color such as red. The waveform of eachdelivered pulse is displayed on the touchscreen interface. A graphicrepresentation of the pre and post impedance between electrodes involvedin the sequence can also be shown on the interface, and this data can beexported for file storage.

In some embodiments, an impedance map can be generated based on voltageand current recordings across anode-cathode pairs or sets of electrodes,and an appropriate set of electrodes that are best suited for ablationdelivery in a given region can be selected based on the impedance map ormeasurements, either manually by a user or automatically by the system.Such an impedance map can be produced, for example, by the feedbackmodule 905, or any other suitable portion of the electrode controller900. For example, if the impedance across an anode/cathode combinationof electrodes is a relatively low value (for example, less than 25Ohms), at a given voltage the said combination would result inrelatively large currents in the tissue and power dissipation in tissue.In such circumstances, this electrode combination would then be ruledout (e.g., via the selection module 912) for ablation due to safetyconsiderations, and alternate electrode combinations would be sought bythe user. In a preferred embodiment, a pre-determined range of impedancevalues, for example 30 Ohms to 300 Ohms, could be used as an allowedimpedance range within which it is deemed safe to ablate. Thus, in someembodiments, an electrode controller can automatically determine asubset of electrodes to which voltage pulses should be applied.

The waveforms for the various electrodes can be displayed and recordedon the case monitor and simultaneously outputted to a standardconnection for any electrophysiology (EP) data acquisition system. Withthe high voltages involved with the device, the outputs to the EP dataacquisition system needs to be protected from voltage and/or currentsurges. The waveforms acquired internally can be used to autonomouslycalculate impedances between each electrode pair. The waveformamplitude, period, duty cycle, and delay can all be modified, forexample via a suitable Ethernet connection. Pacing for the heart iscontrolled by the device and outputted to the pacing leads and aprotected pacing circuit output for monitoring by a lab.

While a touchscreen interface is one preferred embodiment, other userinterfaces can be used to control the system such as a graphical displayon a laptop or monitor display controlled by a standard computer mouseor joystick. FIG. 4 shows a schematic rendering of a portion of the userinterface of the electroporation system. The four windows A, B, C and Dshown in the FIG. represent four different choices of electrode subsetsfor anode and cathode selection. The PV isolation ablation catheter isrepresented by a string of numbered electrodes as indicated by 41,wrapped around the area 42 of the pulmonary veins represented by theenclosed region in this schematic diagram. Referring to B in the FIG.,the dashed-line vectors 46 represent approximate current vectors, withtheir tips at the cathodes and tails or bases at the anodes; in thisFIG., the three electrodes marked 43 are cathodes, and the singleelectrode marked 44 is the anode. The windows A, C and D in this FIG.show other choices of cathode and anode electrode subsets, in each casewith accompanying approximate current density vectors shown by dashedarrows. It is clear from the FIG. that the user can select varioussubsets of electrodes as cathode or anode, depending on the region to beablated along the length of the PV isolation catheter. In oneembodiment, the user can make one selection of cathode and anodesubsets, and the system can take this selection as input to generate anablation sequence that moves around the ring or contour defined by theshape of the PV isolation catheter, for example moving clockwise at eachstep with a one-electrode displacement. In this manner, the pair ofcathode and anode electrode subsets can be sequentially updated forablation purposes, so that if there are N electrodes, after N updatesthe entire contour has been updated such that the tips of the currentarrows shown as 46 have swept once around the contour completely.

In some cases, the portion of the PV isolation catheter with electrodesmay be longer than needed to wrap around a given patient's pulmonaryveins; in this event, a smaller number of electrodes suffices to wraparound the contour of the pulmonary veins. These define the number of“active” electrodes to be used in the ablation process. In the specificexample shown in FIG. 5 for a 30-electrode PV isolation catheter, theset of electrodes wrapped around the pulmonary veins, represented by 51,are the electrodes that would be used in the ablation process, and arecalled out by the label 50 as the set of active electrodes, while theremaining five electrodes represented by 52 are not used in the ablationprocess as they are not located in suitable positions.

In one embodiment of the electroporation system disclosed herein,multiple catheters could be used for ablation, with anode and cathodesubsets respectively chosen to lie on different catheters. In oneexemplary use of such multi-device electroporation, two catheters areconnected to the controller unit of the electroporation system. In someinstances of ablation procedures for the treatment of AtrialFibrillation (AF), in addition to isolating the pulmonary veins, it isalso useful to generate an ablation line that separates or isolatesregions around the mitral valve. Such a line is often termed a “MitralIsthmus Line,” and is a line running from an Inferior aspect of the PVisolation contour to the outer edge of the mitral valve in the leftatrium. In some embodiments, a method of use of the systems describedherein includes inserting a coronary sinus catheter with multipleelectrodes into the coronary sinus. As shown in FIG. 6, electrodesmarked as 66 on the coronary sinus catheter 63, and electrodes marked as65 on the PV isolation catheter 62, are further selected as activesubsets of electrodes for ablation, as indicated in the indicationwindow 61 for the anode and cathode subsets. Thus in effect theelectrodes of the coronary sinus catheter 63 are utilized to define themitral isthmus line, and irreversible electroporation ablation can beeffectively performed on the left atrial wall to generate a mitralisthmus ablation line.

In a some embodiments, the system (any of the generators and controllersdescribed herein) can deliver rectangular-wave pulses with a peakmaximum voltage of about 5 kV into a load with an impedance in the rangeof 30 Ohm to 3000 Ohm for a maximum duration of 200 μs, with a 100 μsmaximum duration being still more preferred. Pulses can be delivered ina multiplexed and synchronized manner to a multi-electrode catheterinside the body with a duty cycle of up to 50% (for short bursts). Thepulses can generally be delivered in bursts, such as for example asequence of between 2 and 10 pulses interrupted by pauses of between 1ms and 1000 ms. The multiplexer controller is capable of running anautomated sequence to deliver the impulses/impulse trains (from the DCvoltage signal/impulse generator) to the tissue target within the body.The controller system is capable of switching between subsets/nodes ofelectrodes located on the single use catheter or catheters (around orwithin the heart). Further, the controller can measure voltage andcurrent and tabulate impedances in each electrode configuration (fordisplay, planning, and internal diagnostic analysis). It can alsogenerate two channels of cardiac pacing stimulus output, and is capableof synchronizing impulse delivery with the internally generated cardiacpacing and/or an external trigger signal. In one embodiment, it canprovide sensing output/connection for access to bio potentials emanatingfrom each electrode connected to the system (with connectivitycharacteristics being compatible with standard electrophysiologicallaboratory data acquisition equipment).

In a some embodiments, the controller (e.g., the controller 900) canautomatically “recognize” the single-use disposable catheter when it isconnected to the controller output (prompting internal diagnostics anduser interface configuration options). The controller can have at leasttwo unique output connector ports to accommodate up to at least twocatheters at once (for example, one 30-electrode socket and one10-electrode socket; a 2-pole catheter would connect to the 10-polesocket). The controller device can function as long as at least onerecognized catheter is attached to it. In a preferred embodiment, thecontroller can have several sequence configurations that provide theoperator with at least some variety of programming options. In oneconfiguration, the controller can switch electrode configurations of abipolar set of electrodes (cathode and anode) sequentially in aclockwise manner (for example, starting at step n, in the next step ofthe algorithm, cathode n+1 and anode n+1 are automatically selected,timed to the synchronizing trigger). With the 30-pole catheter theelectrodes are arranged in a quasi-circumference around the target. Thusin the first sequence, pulse delivery occurs so that the vector ofcurrent density changes as the automated sequencing of the controllerswitches “on” and “off” between different electrodes surrounding thetissue target sequence. The current density vectors generally cross thetarget tissue but in some configurations the current density could beapproximately tangential to the target. In a second sequenceconfiguration, the impulses are delivered to user-selected electrodesubsets of catheters that are connected to the device (the vector ofcurrent density does not change with each synchronized delivery). Athird sequence configuration example is a default bipolar pulse sequencefor the simplest 2-pole catheter. The user can also configure thecontroller to deliver up to 2 channels of pacing stimulus to electrodesconnected to the device output. The user can control the application ofDC voltage with a single handheld switch. A sterile catheter orcatheters can be connected to the voltage output of the generator via aconnector cable that can be delivered to the sterile field. In oneembodiment, the user activates the device with a touch screen interface(that can be protected with a single-use sterile transparent disposablecover commonly available in the catheter lab setting). The generator canremain in a standby mode until the user is ready to apply pulses atwhich point the user/assistant can put the generator into a ready modevia the touchscreen interface. Subsequently the user can select thesequence, the active electrodes, and the cardiac pacing parameters.

Once the catheter has been advanced to or around the cardiac target, theuser can initiate electrically pacing the heart (using a pacing stimulusgenerated by the ablation controller or an external source synchronizedto the ablation system). The operator verifies that the heart is beingpaced and uses the hand-held trigger button to apply the synchronizedbursts of high voltage pulses. The system can continue delivering theburst pulse train with each cardiac cycle as long as the operator isholding down a suitable “fire” button or switch. During the applicationof the pulses, the generator output is synchronized with the heartrhythm so that short bursts are delivered at a pre-specified intervalfrom the paced stimulus. When the train of pulses is complete, thepacing continues until the operator discontinues pacing.

FIG. 7 shows a portion of a graphical user interface according to anembodiment for focal ablation with a bipolar or 2-electrode catheter. Insome embodiments, the graphical user interface can be a touchscreeninterface. A graphical icon 71 for a bipolar catheter is shown alongwith a depth selection button 72 for selecting a desired ablation depth.In one embodiment of the system, based on the latter depth setting, thesystem can select an appropriate voltage value to apply in order toensure that an electric field sufficient to cause irreversibleelectroporation is applied up to the desired depth.

In some embodiments, a pacing selection interface on a portion of theuser interface of the electroporation system is shown in FIG. 8. Thepacing selection interface has various options such as an overdrivepacing option 81 for pacing at a faster-than-normal heart rate, anexternal trigger option 82 for pacing from an externally generatedtrigger, and a diagnostic pacing option 83. By clicking the “Select”button for a given option, that option is selected.

As an example of a pacing option selected, FIG. 9 shows a portion theuser interface of the electroporation system with pacing from anexternal trigger selected for the pacing option. The selected option 86is displayed along with the pacing characteristics and waveform 87 forthe user to visualize.

FIG. 10 shows a portion the user interface of the electroporation systemfor selection of anode and cathode electrodes, with two cathetersconnected to the system. One of the catheters is a PV isolation catheter91 while the other is a multi-electrode catheter 92. The buttons 93 and94 can implement the selection of marked electrode subsets on thecatheters as respectively anode or cathode. Once the selection is made,the appropriate electrodes are colored differently to indicate anode orcathode electrode as shown marked respectively as 96 and 97 in FIG. 11.

The controller and generator can output waveforms that can be selectedto generate a sequence of voltage pulses in either monophasic orbiphasic forms and with either constant or progressively changingamplitudes. FIG. 12 shows a rectangular wave pulse train where thepulses 101 have a uniform height or maximum voltage. FIG. 13 shows anexample of a balanced biphasic rectangular pulse train, where eachpositive voltage pulse such as 103 is immediately followed by a negativevoltage pulse such as 104 of equal amplitude and opposite sign. While inthis example the biphasic pulses are balanced with equal amplitudes ofthe positive and negative voltages, in other embodiments an unbalancedbiphasic waveform could also be used as may be convenient for a givenapplication.

Yet another example of a waveform or pulse shape that can be generatedby the system is illustrated in FIG. 14, which shows a progressivebalanced rectangular pulse train, where each distinct biphasic pulse hasequal-amplitude positive and negative voltages, but each pulse such as107 is larger in amplitude than its immediate predecessor 106. Othervariations such as a progressive unbalanced rectangular pulse train, orindeed a wide variety of other variations of pulse amplitude withrespect to time can be conceived and implemented by those skilled in theart based on the teachings herein.

The time duration of each irreversible electroporation rectangularvoltage pulse could lie in the range from 1 nanosecond to 10milliseconds, with the range 10 microseconds to 1 millisecond being morepreferable and the range 50 microseconds to 300 microseconds being stillmore preferable. The time interval between successive pulses of a pulsetrain could be in the range of 10 microseconds to 1 millisecond, withthe range 50 microseconds to 300 microseconds being more preferable. Thenumber of pulses applied in a single pulse train (with delays betweenindividual pulses lying in the ranges just mentioned) can range from 1to 100, with the range 1 to 10 being more preferable. As described inthe foregoing, a pulse train can be driven by a user-controlled switchor button, in one embodiment preferably mounted on a hand-heldjoystick-like device. In one mode of operation a pulse train can begenerated for every push of such a control button, while in an alternatemode of operation pulse trains can be generated repeatedly during therefractory periods of a set of successive cardiac cycles, for as long asthe user-controlled switch or button is engaged by the user.

In one embodiment of a biphasic waveform, a brief pre-polarization pulsecan be applied just prior to the application of a polarizing rectangularpulse. The rapid change in electric field in tissue, in addition to theelectric field magnitude, driven by this type of pulse applicationincorporating a pre-polarizing pulse can promote a more rapid andeffective tissue ablation in some applications. A schematic diagram of avoltage/signal generator for the purpose of generating such a waveformemploying intrinsic amplification of voltage spikes arising fromswitching is given in FIG. 15. A DC voltage is generated from thedischarge of a suitable capacitor bank 111 (powered by a suitablecharging circuit that is not shown and that would be familiar to thoseskilled in the art) with a suitable high-voltage diode or rectifier 112serving to ensure voltage polarity. While in one embodiment of thesignal generator the voltage discharge passes initially through asnubber or transient-suppression circuit 113 that strongly suppressestransients, in an alternate embodiment an alternate signal path isavailable via a switch unit 116 that detects and lets through a briefinitial voltage spike after a possible voltage inversion. The signalthen passes through an Insulated Gate Bipolar Transistor (IGBT)high-power switch 115 and is accessible at terminals 117 for connectionto catheter electrodes. When no pre-polarizing pulse is required, theswitch unit 116 would not be present, and the signal passes (aftertransient-suppression in the snubber circuit 113) initially through aMetal Oxide Semiconductor Field Effect Transistor (MOSFET) switch 114before passing through the IGBT switch 115. The IGBT interfaces betterwith a wider range of load impedances (from tissue), while the fasterswitching speed of the MOSFET can drive a suitably fast turn-on/turn-offof the IGBT switch, so that using them in the sequence shown in FIG. 15can be advantageous.

In order to generate a sequence of rectangular pulses, the time constantassociated with the capacitor bank discharge is chosen to besignificantly longer than an individual pulse duration. If the chargingcircuit of the capacitor bank is much more rapid, a sequence of veryhighly rectangular pulses can be generated from repeated capacitor bankdischarges. As shown in FIG. 16, when a capacitor bank is suddenlydischarged by closing a switch, the voltage can briefly be amplified andspike as indicated by 122 before settling to a normal discharge pattern121. The inductance of leads connected to the capacitor forms a tankcircuit with the capacitor, and in many cases this tank circuit israpidly driven to resonance by the discharge, leading to the voltageamplification seen in the spiking behavior 122. Indeed, by suitablycontrolling lead inductance and resistance, the extent of spikegenerated (spike amplitude and duration) can be further controlled. Suchadditional inductance/resistance or spike control circuitry can beincluded in the switch unit 116 shown in FIG. 15. Thus the switch 116plays a gatekeeping role akin to the notion of “Maxwell's demon” instatistical physics, allowing the passage of some types of intrinsicallyamplified voltage spikes, and accordingly the signal generator of FIG.15 can also be termed a Maxwell amplifier.

A schematic representation of a biphasic pulse with pre-polarization isshown in FIG. 17, where each rectangular polarizing pulse such as 125 ispreceded by a pre-polarizing negative voltage spike 126 derived fromtransient spiking from a generator of the type shown in FIG. 15. Thevalue of the negative spike voltage peak V_(L) could be determined bythe spike control circuitry of the switch unit 116 as discussed above.The biphasic pulses involve a time duration T₁ for the pre-polarizingspike, a duration T₂ for the rectangular polarizing pulse, with a timedelay T_(d) indicated by 127 in FIG. 17 between successive biphasicpulses. Typical values of T₂ could be of the order of 100 microseconds,while T₁ could lie in the range 5 microseconds to 50 microseconds andthe delay time T_(d) could be in the range 100 microseconds to 300microseconds. All of these parameters can be determined by the design ofthe signal generator, and in various embodiments could also bedetermined by user control as may be convenient for a given clinicalapplication. The specific examples and descriptions herein are exemplaryin nature and variations can be developed by those skilled in the artbased on the material taught herein without departing from the scope ofthe embodiments described herein.

A catheter device for focal ablation with the electroporation systemaccording to an embodiment is shown schematically in FIG. 18A. The focalablation catheter 131 has two electrodes disposed in the distal sectionof the catheter, with a relatively proximally placed cathode electrode133 of length L₁ exposed on the catheter shaft and a relatively distallyplaced anode electrode 134 of length L₂ mounted on the inner section ofthe shaft. The catheter shaft is made of a material with high dielectricstrength such as for example a polymer comprising Teflon. Thus thedistal electrode 134 is covered by the polymeric shaft and is notexposed to the blood pool on the shaft exterior. Both electrodes aremetallic, and in one embodiment the anode could be poly-metallic inconstruction, for example comprising regions of Titanium and regions ofPlatinum.

As shown in FIG. 18B, the anode 141 is recessed from the distal tip, andcould be placed with its distal portion between 0.5 mm and 10 mm awayfrom the distal end of the catheter. While the recessed and interiorplacement of the anode electrode is counterintuitive, it can be aneffective means of enhancing electroporation efficacy and safetyselectively for focal ablation. As indicated in the FIG., theschematically depicted (negative) current density flowing from thecathode to the anode indicated by the stream of arrows 142 bends aroundthe distal edge 143 of the catheter shaft resulting in a region of highcurvature of the current density, and correspondingly curved electricfield lines as well. If the anode electrode is recessed, the highestcurvature region at the edge of the electrode where the strongestelectric field occurs is also displaced proximally, so that the electricfield around the distal tip of the catheter itself is not so large as tocause any increased local heating, while remaining large enough to causeirreversible electroporation. FIG. 18C schematically shows electricfield lines 152 as they curve to enter the distal catheter end 151,resulting in a zone or region 153 distal to the catheter with arelatively uniform electric field. The electric field in this regionwould not be as uniform with a standard, externally placed electrode onthe catheter, and further would generally have regions of very highintensity. The recessed interior placement of the distal electrodetherefore results in superior and safe electroporation ablation deliveryfor focal ablation in a selective zone distal to the catheter tip. Whilein one embodiment the anode electrode can be a hollow ring, in otherembodiments it could have a different form such as a cylinder withmultiple longitudinal holes or channels.

In some embodiments, the interior lumen of the catheter can carry afluid delivered out through the distal end of the catheter. The fluidcan be an ionic fluid such as isotonic or hypertonic saline and canenhance electrical conductivity in the distal region of the catheter andbeyond the distal end ensuring a proper and more uniform distribution oflocal electric field in a distal region around the catheter. As shown inFIG. 18D, the inner lumen 163 of the catheter carries a flowing fluidindicated by the arrows, while the anode 161 is in the shape of acylinder that has longitudinal channels through which fluid can flow.The anode electrode is shown in cross section 162 where the multiplethrough-channels are visible. The saline or ionic fluid deliveredthrough the channels can act as an ion bridge through which goodelectrical current conduction is possible in the vicinity of thecatheter's distal end, resulting in a more uniform distribution of localelectric field and electroporation energy delivery. Further, the flow ofsaline fluid itself can dislodge tissue debris or any bubbles generatedby the electroporation-driven breakdown of tissue in the region aroundthe distal catheter tip. In one embodiment, ultrasonic wavesschematically shown as 164 in FIG. 18D can be applied to the fluid tofurther ensure that any bubbles that may be lodged on the cathetersurface in its distal region are dislodged, again for purposes ofmaintaining relative uniformity of the local electric field. Theultrasonic waves or ultrasound through the fluid can be generated bysuitable piezoelectric transducers mounted more proximally along theshaft of the catheter, or even within the catheter handle. In oneembodiment, ultrasound generation is coordinated with electroporation DCvoltage application so that the kinetic energy of focused ultrasound isavailable “on demand.”

The above statements of the advantages of the recessed inner electrodefor the focal ablation catheter have been verified by the inventors inphysically realistic simulations. FIG. 19A shows a simulation geometryof a catheter 601 in a blood pool region 602 and abutting a myocardiumregion 603 adjacent to a pericardial region 605, all regions beingassumed cylindrical for the simulation; the section or plane 611 waschosen to plot electric field intensity contours. Further the myocardiumregion has a region of scar tissue 604 distal to the catheter. FIG. 19Bshows the catheter's distal region with distal tip 612, distal (anode)recessed electrode 615 mounted internal to the shaft, and a proximal(cathode) electrode 616. With a DC voltage of 1000 Volts applied betweenthe electrodes and using realistic physical property values, theresulting electric field intensity contours are illustrated in FIG. 19C,which shows the geometry and the contours in the section 611 of FIG.19A. The cathode 616 and recessed anode 615 are indicated in FIG. 19C,as are the blood pool region 602, the myocardium region 603 and thepericardial region 605. The electric field intensity contourscorresponding to 1000 Volts/cm, 500 Volts/cm and 200 Volts/cmrespectively are shown as contours 617, 618 and 619 respectively.

FIG. 19D repeats the electric field simulation for a catheter with bothelectrodes mounted externally, showing the distal anode 622 and proximalcathode 623 in the same tissue geometry. As before, with a DC voltage of1000 Volts applied between the electrodes and using the same realisticphysical property values, the resulting electric field intensitycontours corresponding to 1000 Volts/cm, 500 Volts/cm and 200 Volts/cmrespectively are shown as contours 626, 627 and 628 respectively.

Comparing the intensity contours of FIG. 19C and FIG. 19D, it is clearthat the former FIG. shows a relatively more uniform intensitydistribution in the myocardium region where excessively large electricfield values (500 Volts/cm or more) are present to a much lesser extent,mitigating the possibility of locally large electric current densitiesand corresponding temperature increases.

The focal ablation catheter described above in various embodiments couldbe used in cardiac applications such as ablation delivery to treatVentricular Tachycardia (VT), where targeted ablation delivery could beof great benefit. In one embodiment, the length L₂ of the distal anodeelectrode could be significantly longer than the length L₁ of theproximal cathode electrode. The ratio L₂/L₁ could have a value of atleast 1.3, more preferably lie in the range 1.3 to 10, and still morepreferably in the range 2 to 5. The increased surface area of theexposed inner surface of the anode electrode can serve to reduce thecurrent density near it, thereby enhancing safety and enhancing theefficacy of ion bridging current transfer with the saline fluidinfusion. In addition or as an alternate method to reduce high currentdensity due to exposed metal regions with high curvature, the edges ofthe electrode can be beveled or rounded to ensure that there are nosharp corners or regions with high curvature.

Thus, the methods described herein allow for a variety of approaches inthe context of cardiac ablation. Considering for example the treatmentof Ventricular Tachycardia (VT) as a clinical application,electroporation ablation of cardiac tissue could be performed across apair of nearby electrodes respectively on one or more epicardiallyplaced catheters in one embodiment. In an alternate embodiment, a singlefocal ablation endocardial catheter such as described above can be usedto ablate on the endocardial side of a cardiac chamber. In still anotheralternate embodiment, a bipolar pair of electrodes on differentcatheters, one placed endocardially and the other epicardially could beused to drive irreversible electroporation.

A balloon ablation device for use with the electroporation systemaccording to an embodiment is schematically illustrated in FIG. 20.While the device is shown to be situated in a blood vessel 301, it canalso be used in other anatomical areas such as a cardiac ventricle. Thedevice shaft 302 has an inflatable balloon 306 disposed in its distalportion. On either side of the balloon and mounted on the shaft are aproximal cathode electrode 303 and a distal anode electrode 304. Theballoon surface 305 is coated with a thin layer of a good insulator suchas a biocompatible metal oxide (for example, aluminum oxide). When airis pumped in through the catheter shaft lumen and through appropriateopenings (not shown) from the shaft into the balloon, the balloon caninflate, as the inflated shape in FIG. 20 depicts. In ventricularapplications such as cardiac ablation for VT, the balloon can serve todisplace collateral structures away from the distal end of the catheter.Since the balloon surface is an insulator, when a DC voltage is appliedbetween the electrodes, the current flow between electrodes and throughthe tissue is deflected around the balloon. The electric field is alsocorrespondingly deflected around the surface of the balloon, and curvesoutward and can extend into the wall of the blood vessel, as shown bythe schematic electric field lines 308 in the FIG. In one embodiment,the distal electrode 304 can be mounted on the outside of the shaft withexternal surface exposed, for intravascular ablation applications suchas for example peripheral vascular applications for treatment ofatherosclerosis where it is desired to ablate the vessel wall region orclear deposits. In an alternate embodiment, the distal electrode 304 canbe mounted on the inner side of the catheter shaft, so that the metalelectrode is internally exposed. Furthermore, the distal electrode couldbe recessed from the distal tip, as schematically shown in FIG. 20. Sucha device could be used in focal ablation applications.

An alternate preferred embodiment of a balloon ablation device for usewith the electroporation system according to an embodiment is shownschematically in FIG. 21A. As before, while the device is shown to besituated in a blood vessel 172, it can also be used in other anatomicalareas such as a cardiac ventricle. The device shaft 171 has aninflatable balloon 177 disposed in its distal portion. On either side ofthe balloon and mounted on the shaft are a proximal cathode electrode173 and a distal anode electrode 174. The balloon surface 176 is coatedwith a thin layer of a good insulator such as a biocompatible metaloxide (for example, aluminum oxide). When fluid is pumped in through thecatheter shaft lumen, the balloon can inflate, as the inflated shape inFIG. 21A depicts. The region of the shaft within the balloon can have atleast one ultrasonic transducer 175 mounted thereon. Further, while theinterior of the balloon is inflated with fluid, the wall 178 of theballoon has a varying cross section and is filled with a gas such asair. Thus there is a liquid-gas interface at the wall of the balloon.This interface can act as a mirror or reflecting surface for ultrasound.As illustrated in the FIG., ultrasound rays 179 emitted by thetransducer 175 are reflected at the wall of the balloon and aresubsequently focused on a ring-like region, shown with its annularregions 181 in a plane 180 and viewed edge-on in the illustration. Theannular region external to the balloon where the ultrasound is focusedis shown in FIG. 21B as the dark annulus 203 surrounding the vessel wall201, shown in cross section. When high-intensity ultrasound generated bythe transducer in the catheter is focused in this manner, its energy isdeposited in the annulus as heat and raises temperature locally. Theirreversible electroporation threshold of tissue is temperaturedependent and is lowered with increasing temperature. Thus in theannular region where temperature is increased due to the focusedultrasound, the electroporation threshold is decreased, and a relativelyweaker electric field in this region can still generate irreversibleelectroporation, permitting selective tissue ablation.

As before, in ventricular applications such as cardiac ablation for VT,the balloon can serve to displace collateral structures away from thedistal end of the catheter. Since the balloon surface is an insulator,when a DC voltage is applied between the electrodes, the current flowbetween electrodes and through the tissue is deflected around theballoon. The electric field is also correspondingly deflected around thesurface of the balloon, and curves outward and can extend into the wallof the blood vessel, as shown by the schematic electric field lines 191in the FIG. With the lowered irreversible electroporation threshold inthe annular region of focused ultrasound in the vessel wall, theelectric field in the annular region is sufficient to selectively driveirreversible electroporation. In one embodiment, the distal electrode174 can be mounted on the outside of the shaft with external surfaceexposed, for intravascular ablation applications such as for exampleperipheral vascular applications for treatment of atherosclerosis whereit is desired to ablate the vessel wall region or clear deposits. In analternate embodiment, the distal electrode 174 can be mounted on theinner side of the catheter shaft, so that the metal electrode isinternally exposed. Furthermore, the distal electrode could be recessedfrom the distal tip, as schematically shown in FIG. 21A. Such a devicecould be used in focal ablation applications.

While the specific embodiment of the balloon ablation device describedabove utilizes high-intensity focused ultrasound to selectively generatetemperature increases in a given region in order to decrease theelectroporation threshold, it must be noted that alternate energydelivery mechanisms such as microwaves could be utilized for the purposeof increasing tissue temperature by energy deposition in order todecrease the irreversible electroporation threshold electric field. Theballoon ablation devices described in the foregoing could also be usedin pulmonary outflow tract applications to treat pulmonary hypertension,or in eosophageal or gastrointestinal applications where tissue ablationis an appropriate therapy.

An ablation device for irreversible electroporation in the form of anexpanding basket catheter is schematically illustrated in FIG. 22.Mounted on the shaft 501 of the device is a sliding member 505 which isattached to a system of struts 507. While the system of struts isinitially substantially aligned with the length of the shaft in a foldedconfiguration (not shown), it can unfold or open out like an umbrella bymovement of the sliding member 505 along the shaft, resulting in thebasket-like unfolded structure shown in FIG. 23. For purposes ofclarity, the system of struts is only partially shown in the FIG. Thebasket construction or set of expanding struts can comprise asuperelastic alloy such as for instance an alloy of Nickel and Titaniumoften called Nitinol®; such a construction can be of use in a largevessel where a significant amount of expansion could be called for. Oneither side of the basket-like structure and disposed along the shaftare two electrodes 502 and 503. Bead-like electrodes 508 are present atcorners of the strut assembly. The device be guided to a desiredlocation inside a large vascular or other anatomical vessel (forexample, the pulmonary outflow tract), positioned suitably and thenunfolded. Subsequently, irreversible electroporation ablation can beapplied with the electrodes on the basket device.

In one embodiment the basket catheter with struts folded can have alumen for passage of a suitable guidewire which could be used as adelivery system for appropriate placement of the basket catheter.Various choices of electrode configurations for ablation are possiblefor this device. In one preferred embodiment, either of electrodes 502or 503 is selected as cathode, while the beads 508 are selected asanodes. With such a choice, a region of vessel wall that is located justproximal to or just distal to the beads can be selectively ablated,depending on whether electrode 502 or electrode 503 respectively isactivated as cathode. The rounded shape of the beads and their locationon the outer edge of the basket (and thus close to the vessel wall)results in good ablation characteristics at the vessel wall. The voltageapplied can be suitably selected so that an appropriate electric fieldis generated in the ablative region near the bead electrodes. Inalternate preferred embodiments, the basket catheter can furtherincorporate energy sources such as focused ultrasound or microwaves inorder to selectively raise temperatures in localized regions and therebylower the irreversible electroporation threshold.

In some embodiments, a method includes identifying, via a selectionmodule of an electrode controller, a set of anode/cathode pairs from aset of electrodes of a multi-electrode catheter. The method can beperformed using any suitable controller, such as for example, thecontroller 900 described above. The multi-electrode catheter isconfigured to be disposed about a portion of a heart. At least one ofthe anode/cathode pair including at least one anode electrode and atleast one cathode electrode. In other embodiments, however, theanode/cathode pair can include multiple anode electrodes or cathodeelectrodes. In some embodiments, the identifying can be based on inputreceived from an input/output module of the electrode controller (e.g.,manual input). In other embodiments, the identifying can be based on apredetermined schedule of electrodes. In yet other embodiments, theidentifying can be performed automatically based on an impedance map asdescribed herein.

The method further includes conveying a pacing signal to a pacing leadconfigured to be operatively coupled to the heart, and receiving, at afeedback module of the electrode controller, an electrocardiographsignal associated with a function of the heart.

The method further includes delivering, via a pulse delivery module ofthe electrode controller, a pulsed voltage waveform to the plurality ofanode/cathode pairs according to a sequential pattern.

Some embodiments described herein relate to a computer storage productwith a non-transitory computer-readable medium (also can be referred toas a non-transitory processor-readable medium) having instructions orcomputer code thereon for performing various computer-implementedoperations. The computer-readable medium (or processor-readable medium)is non-transitory in the sense that it does not include transitorypropagating signals per se (e.g., a propagating electromagnetic wavecarrying information on a transmission medium such as space or a cable).The media and computer code (also can be referred to as code) may bethose designed and constructed for the specific purpose or purposes.Examples of non-transitory computer-readable media include, but are notlimited to: magnetic storage media such as hard disks, floppy disks, andmagnetic tape; optical storage media such as Compact Disc/Digital VideoDiscs (CD/DVDs), Compact Disc-Read Only Memories (CD-ROMs), andholographic devices; magneto-optical storage media such as opticaldisks; carrier wave signal processing modules; and hardware devices thatare specially configured to store and execute program code, such asApplication-Specific Integrated Circuits (ASICs), Programmable LogicDevices (PLDs), Read-Only Memory (ROM) and Random-Access Memory (RAM)devices.

Examples of computer code include, but are not limited to, micro-code ormicro-instructions, machine instructions, such as produced by acompiler, code used to produce a web service, and files containinghigher-level instructions that are executed by a computer using aninterpreter. For example, embodiments may be implemented usingimperative programming languages (e.g., C, Fortran, etc.), functionalprogramming languages (Haskell, Erlang, etc.), logical programminglanguages (e.g., Prolog), object-oriented programming languages (e.g.,Java, C++, etc.) or other suitable programming languages and/ordevelopment tools. Additional examples of computer code include, but arenot limited to, control signals, encrypted code, and compressed code.

While various specific examples and embodiments of systems and tools forselective tissue ablation with irreversible electroporation weredescribed in the foregoing for illustrative and exemplary purposes, itshould be clear that a wide variety of variations and alternateembodiments could be conceived or constructed by those skilled in theart based on the teachings herein. While specific methods of control andDC voltage application from a generator capable of selective excitationof sets of electrodes were disclosed, persons skilled in the art wouldrecognize that any of a wide variety of other control or user inputmethods and methods of electrode subset selection etc. can beimplemented without departing from the scope of the present invention.Likewise, while the foregoing described a range of specific tools ordevices for more effective and selective DC voltage application forirreversible electroporation through ionic fluid irrigation andultrasonic agitation, including insulating balloon constructions, focalablation tools, and a basket catheter with a multiplicity of, otherdevice constructions or variations could be implemented by one skilledin the art by employing the principles and teachings disclosed hereinwithout departing from the scope of the present invention, in thetreatment of cardiac arrhythmias, in intravascular applications, or avariety of other medical applications.

Furthermore, while the present disclosure describes specific embodimentsand tools involving irrigation with saline fluids and the use oftemperature to selectively ablate tissue by taking advantage of thetemperature-dependence of the threshold of irreversible electroporation,it should be clear to one skilled in the art that a variety of methodsand devices for steady fluid delivery, or for tissue heating through thedelivery of focused kinetic energy or electromagnetic radiation could beimplemented utilizing the methods and principles taught herein withoutdeparting from the scope of the present invention.

Where schematics and/or embodiments described above indicate certaincomponents arranged in certain orientations or positions, thearrangement of components may be modified. For example, although thecontroller 900 is shown as optionally including the pacing module 902,in other embodiments, the controller 900 can interface with a separatepacing module. Similarly, where methods and/or events described aboveindicate certain events and/or procedures occurring in certain order,the ordering of certain events and/or procedures may be modified.

Although various embodiments have been described as having particularfeatures and/or combinations of components, other embodiments arepossible having a combination of any features and/or components from anyof embodiments as discussed above.

The invention claimed is:
 1. A method, comprising: determining, via afeedback module of an electrode controller, an impedance betweenelectrodes from a plurality of electrodes of a multi-electrode catheter,the multi-electrode catheter being disposed about a portion of a heartsuch that the electrodes are separated by a blood pool of a cardiacchamber, the impedance being indicative of an impedance throughintervening blood; identifying, via a selection module of the electrodecontroller, a plurality of anode-cathode pairs from the plurality ofelectrodes based on the impedance between the electrodes being within apredetermined safety range for ablation, each anode-cathode pair of theplurality of anode-cathode pairs including at least one electrodeidentified as an anode and at least one electrode identified as acathode, the predetermined safety range being 30 Ohms to 300 Ohms;conveying a pacing signal to a pacing lead configured to be operativelycoupled to the heart; and delivering, via a pulse delivery module of theelectrode controller, a pulsed voltage waveform to the plurality ofanode-cathode pairs according to a sequential pattern such that theplurality of anode-cathode pairs generates one or more electric fieldshaving a threshold strength of at least about 200 Volts/cm for ablatingcardiac tissue of the heart, the pulsed voltage waveform including apre-polarizing pulse immediately followed by a polarizing pulse, thepre-polarizing pulse being of a shorter duration than the polarizingpulse, the pre-polarizing pulse being generated by using a switch unitto detect and pass an initial voltage spike generated from switching ona discharge of a capacitor bank.
 2. The method of claim 1, furthercomprising: generating the sequential pattern based on at least one ofthe impedance between the electrodes of each of the plurality ofanode-cathode pairs, a distance between the electrodes of each of theplurality of anode-cathode pairs, or a characteristic associated withthe heart.
 3. The method of claim 1, wherein: the multi-electrodecatheter is a first catheter; the plurality of electrodes is a firstplurality of electrodes; and the identifying includes identifying atleast one anode-cathode pair from the plurality of anode-cathode pairsto include at least one electrode from the first catheter beingidentified as the anode and at least one electrode from a secondcatheter being identified as the cathode, the second catheter beingdistinct from the first catheter.
 4. The method of claim 1, furthercomprising: generating, based at least on the impedance between theelectrodes, an impedance map associated with the plurality of electrodespairs, the identifying being based at least in part on the impedancemap.
 5. The method of claim 1, wherein the pulsed voltage waveform is abiphasic waveform.
 6. The method of claim 1, wherein the pulsed voltagewaveform is a first pulsed voltage waveform, further comprisingdelivering one or more additional pulsed voltage waveforms.
 7. Themethod of claim 1, wherein the pulse delivery module of the electrodecontroller comprises at least one of a transient-suppression circuit anda switch circuit.
 8. The method of claim 1, wherein the at least oneelectrode identified as the anode in at least one anode-cathode pair ofthe plurality of anode-cathode pairs is recessed with respect to asurface of the multi-electrode catheter and wherein the at least oneelectrode identified as the cathode in at least one anode-cathode pairof the plurality of anode-cathode pairs is on the surface of themulti-electrode catheter.
 9. The method of claim 1, further comprising:imaging a first anode-cathode pair of the plurality of anode-cathodepairs to generate an image of the first anode-cathode pair; estimating,based on the image, a distance between the at least one electrodeidentified as the anode of the first anode-cathode pair and the at leastone electrode identified as the cathode of the first anode-cathode pair;and setting one or more parameters of the electrode controller forirreversible electroporation based on the estimated distance.
 10. Themethod of claim 1, wherein determining the impedance between theelectrodes includes determining an impedance along a current vectorextending from a first electrode from the plurality of electrodes,through first cardiac wall tissue of the cardiac chamber, through theintervening blood, through second cardiac wall tissue of the cardiacchamber, and to a second electrode from the plurality of electrodes. 11.The method of claim 1, wherein the pulse voltage waveform has anamplitude of between 0.5 kV and 10 kV.
 12. A method, comprising:identifying, via a selection module of an electrode controller, aplurality of anode-cathode pairs from a plurality of electrodes of amulti-electrode catheter, the multi-electrode catheter configured to bedisposed about a portion of a heart, at least one anode-cathode pair ofthe plurality of anode-cathode pairs including at least one electrodeidentified as an anode and at least one electrode identified as acathode; conveying a pacing signal to a pacing lead configured to beoperatively coupled to the heart; receiving, at a feedback module of theelectrode controller, an electrocardiograph signal associated with afunction of the heart; and delivering, via a pulse delivery module ofthe electrode controller, a pulsed voltage waveform to the plurality ofanode-cathode pairs according to a sequential pattern to irreversiblyelectroporate tissue, the pulsed voltage waveform including apre-polarizing pulse immediately followed by a polarizing pulse, thepre-polarizing pulse being of a shorter duration than the polarizingpulse, the pre-polarizing pulse being generated by using a switch unitto detect and pass an initial voltage spike generated from switching ona discharge of a capacitor bank.
 13. The method of claim 12, wherein theidentifying is based on an input received from an input/output module ofthe electrode controller.
 14. The method of claim 13, furthercomprising: generating, at the input/output module of the electrodecontroller, a signal associated with a graphical map of the plurality ofelectrodes.
 15. The method of claim 12, wherein the identifying is basedon a predetermined schedule of the plurality of electrodes.
 16. Themethod of claim 12, further comprising: computing an impedance betweenthe at least one electrode identified as the anode in the at least oneanode cathode pair and the at least one electrode identified as thecathode in the at least one anode cathode pair, the identifying beingperformed automatically by the selection module based at least in parton the impedance.
 17. The method of claim 12, wherein the delivering thepulsed voltage waveform includes delivering the pulsed voltage waveformduring a time window based on at least one of the pacing signal and theelectrocardiograph signal.
 18. The method of claim 12, wherein thepre-polarizing pulse and the polarizing pulse have opposite polarities.19. The method of claim 12, wherein the duration of the pre-polarizingpulse is from about 5 to about 50 microseconds and wherein the durationof the polarizing pulse is from about 100 microseconds to about 300microseconds.
 20. The method of claim 12, wherein the pre-polarizingpulse is a continuously varying pulse and wherein the polarizing pulseis a direct current (DC) pulse.